We are studying the molecular mechanisms involved in the pathogenesis of rhabdomyosarcoma (RMS), the most common soft tissue sarcoma of childhood, and osteogenic sarcoma (OS), the most common bone tumor of childhood. Several common growth factors are known to play a role in normal growth and maturation of skeletal muscle and bone such as TGF-beta and insulin- like growth factors (IGF'S). In addition, the tumor suppressor gene p53 has been implicated in the progression of both these tumor types. We have focused our attention on the role of IGFs in these tumors. We have identified ICF II as an autocrine growth factor in RMS and have begun a Phase II study using suramin, an agent that we have demonstrated is capable of interfering with this autocrine growth loop in vitro. In an attempt to determine the precise role of overexpression of IGF II in RMS tumors, we have transfected a human IGF II cDNA expression vector into mouse myoblast cells and are analyzing the effect on differentiation and proliferation potential, as well as tumorigenic potential. To begin to sort out the molecular events that play a role in the metastatic potential of these cells, we have developed a series of subclones from a human embryonal RMS cell line with differing tumorigenic and metastatic potentials when injected into nude mice. Current ongoing experiments to describe molecular differences between the various subclones include subtraction cDNA cloning and differential display of RNA to isolate genes that may confer metastatic behavior to these cells. Other investigators have demonstrated the presence of type I IGF receptors on the surface of OS cells and that IGF I is a mitogen to these cells. We have no demonstrated that OS cell lines require signaling through the IGF I receptor for in vitro growth. Since growth hormone is known to stimulate IGF I secretion and there are data that suggest growth hormone secretion is important in the development of OS, we have just begun a Phase I study using a somatostatin (SST) analog to inhibit GH secretion in patients with metastatic OS. This study will allow us to determine the effect of the drug on stimulated GH as well as circulating IGF I levels in patients with OS. In addition, we have to determine whether OS cells express SST receptors that may mediate a more direct effect of SST analogues on the growth of these tumors.